APPLICANT'S ABSTRACT: My overarching career goal to be achieved through this K23 award is to learn how to integrate pharmacological, molecular genetic, and neuroimaging techniques in the development and assessment of medications for the treatment of alcoholism. To accomplish my goal of becoming an independent physician scientist at the conclusion of the K23 award period, it is important for me to gain proficiency as a general academician and to obtain specific sub-specialty training. My sub-specialty training will be organized under the umbrella of an integrated neuroscience project organized as three experiments requiring knowledge and expertise with the disciplines of pharmacology, neuroimaging, and molecular genetics. My project is based upon understanding the role of serotonergic function as a determinant of drinking behavior in heavy social drinkers. Predicated on the hypothesis that serotonergic function is under genetic control at the 5'-flanking regulatory region (5'-HTTPLR) of the serotonin transporter (SERT), I will study how individuals with the long (LL) form, with up to three times greater uptake of intrasynaptic serotonin (5-HT) and therefore a relative hyposerotonergic state than those with the short or heterozygous form (SS/SL), differ in their ability to appreciate the hedonic effects of alcohol or crave for it when provoked by experimenter generated cues in the human laboratory. I will pharmacologically provoke the serotonergic system, using the tryptophan depletion paradigm, to determine whether alterations in 5-HT availability exacerbates the functional and behavioral differences due to genotypic variation at the SERT. I will use Single Photon Emission Computerized tomography (SPECT) to demonstrate that individuals with the LL form compared with the SS/SL variants have increased SERT density, an index of the functional capacity of the 5-HT system in individuals with these respective genotypes. If these experiments are successful, I may be able to show that genotypic differences between heavy social drinkers can be associated with differential risks of developing the alcoholism disease. This study therefore has the potential to identify a method for delineating heavy social drinkers with the greatest risk for developing the alcoholism disease, and should guide the rational development of specific serotonergic agents for the treatment of alcoholism.